Delayed release rasagiline malate formulation

ABSTRACT

Disclosed are formulations which are designed to delay release of rasagiline while maintaining specific pharmacokinetic properties.

The application claims benefit of U.S. Provisional Application No.61/205,833, filed Jan. 23, 2009, the contents of which are herebyincorporated by reference.

Throughout this application various publications, published patentapplications, and patents are referenced. The disclosures of thesedocuments in their entireties are hereby incorporated by reference intothis application in order to more fully describe the state of the art towhich this invention pertains.

BACKGROUND OF THE INVENTION

U.S. Pat. Nos. 5,532,415, 5,387,612, 5,453,446, 5,457,133, 5,599,991,5,744,500, 5,891,923, 5,668,181, 5,576,353, 5,519,061, 5,786,390,6,316,504, 6,630,514 disclose R(+)-N-propargyl-1-aminoindan (“R-PAI”),also known as rasagiline. Rasagiline has been reported to be a selectiveinhibitor of the B-form of the enzyme monoamine oxidase (“MAO-B”) and isuseful in treating Parkinson's disease and various other conditions byinhibition of MAO-B in the brain.

U.S. Pat. No. 6,126,968 and PCT International Application PublicationNo. WO 95/11016 disclose pharmaceutical formulations comprisingrasagiline. PCT International Application Publication No. WO 2006/014973also discloses pharmaceutical formulations comprising rasagiline.

AZILECT® is a commercially available rasagiline mesylate immediaterelease formulation indicated for the treatment of the signs andsymptoms of idiopathic Parkinson's disease as initial monotherapy and asadjunct therapy to levodopa. The current marketed formulation ofrasagiline (Azilect®) is rapidly absorbed, reaching peak plasmaconcentration (t_(max)) in approximately 1 hour. The absolutebioavailability of rasagiline is about 36%. (AZILECT® Product Label, May2006).

SUMMARY OF THE INVENTION

The subject application provides a stable oral dosage form comprising acore having rasagiline malate and at least one pharmaceuticallyacceptable excipient; and an acid resistant pharmaceutically acceptablecoating.

The subject application also provides a method of treating a patientsuffering from Parkinson's disease comprising administering to thepatient the stable oral dosage form.

DETAILED DESCRIPTION OF THE INVENTION

The subject application provides a stable oral dosage form comprising acore having rasagiline malate and at least one pharmaceuticallyacceptable excipient; and an acid resistant pharmaceutically acceptablecoating.

In an embodiment of the stable oral dosage form, the dosage form wheningested by a human subject provides an AUC value of rasagiline of80-130% of that of the corresponding amount of rasagiline ingested as animmediate release formulation.

In another embodiment of the stable oral dosage form, the dosage formupon administration to a human subject provides an AUC value ofrasagiline of 80-125% of that of the corresponding amount of rasagilineingested as an immediate released formulation.

In yet another embodiment of the stable oral dosage form, the dosageform when ingested by a human subject provides a C_(max) of rasagiline80-145% of that of the corresponding amount of rasagiline ingested as animmediate release formulation.

In yet another embodiment of the stable oral dosage form, the dosageform when ingested by a human subject provides a C_(max) of rasagilineof 80-125% of that of the corresponding dosage of rasagiline ingested asan immediate release formulation.

In yet another embodiment of the stable oral dosage form, the corefurther comprises at least one anti-oxidant.

In yet another embodiment of the stable oral dosage form, theanti-oxidant is malic acid.

In yet another embodiment of the stable oral dosage form, the core is inthe form of a tablet.

In yet another embodiment of the stable oral dosage form, the corefurther comprises at least one disintegrant.

In yet another embodiment of the stable oral dosage form, the corecomprises between 0.5% and 20% by weight of disintegrant.

In yet another embodiment of the stable oral dosage form, thedisintegrant is pre-gelatinized starch.

In yet another embodiment of the stable oral dosage form, the acidresistant coating layer comprises methacrylic acid-ethyl acrylatecopolymer (1:1) and a plasticizer.

In yet another embodiment of the stable oral dosage form, in the acidresistant coating layer the ratio of methacrylic acid-ethyl acrylatecopolymer (1:1) to plasticizer is between 10 to 1 and 2 to 1.

In yet another embodiment of the stable oral dosage form, in the coatingthe ratio of methacrylic acid-ethyl acrylate copolymer (1:1) toplasticizer is 5 to 1.

In yet another embodiment of the stable oral dosage form, theplasticizer is triethyl citrate.

In yet another embodiment of the stable oral dosage form, the acidresistant coating layer further comprises talc.

In yet another embodiment of the stable oral dosage form, the acidresistant coating is between 3% and 12% by weight of the dosage form.

In yet another embodiment of the stable oral dosage form, the acidresistant coating is 8% by weight of the dosage form.

In yet another embodiment of the stable oral dosage form, the acidresistant coating comprises two coating layers.

In yet another embodiment of the stable oral dosage form, the inner oneof the two coating layers comprises hypromellose.

In yet another embodiment of the stable oral dosage form, the dosageform is less than 150 mg by weight.

In yet another embodiment of the stable oral dosage form, the dosageform comprises 0.66 mg to 3.05 mg of rasagiline malate.

In yet another embodiment of the stable oral dosage form, the dosageform in addition to the rasagiline malate comprises mannitol, colloidalsilicon dioxide, starch NF, pregelatinized starch, stearic acid, talc,hypromellose, methacrylic acid ethyl acrylate copolymer, talc extrafine, and triethyl citrate.

In yet another embodiment of the stable oral dosage form, the dosageform comprises 80.0 mg of mannitol, 0.6 mg of colloidal silicon dioxide,10.0 mg of starch NF, 20.0 mg of pregelatinized starch, 2.0 mg ofstearic acid, 2.0 mg of talc, 4.8 mg of hypromellose, 6.25 mg ofmethacrylic acid-ethyl acrylate copolymer, 1.25 mg of triethyl citrate,and 3.1 mg of talc extra fine.

In yet another embodiment of the stable oral dosage form, the dosageform comprises 67.8 mg of mannitol, 0.6 mg of aerosil, 10.0 mg of starchNF, 20.0 mg of pregelatinized starch, 2.0 mg of stearic acid, 2.0 mg oftalc, 4.8 mg of hypromellose, 4.0 mg of methacrylic acid ethyl acrylatecopolymer, 0.8 mg of triethyl citrate, and 1.9 mg of talc extra fine.

In yet another embodiment of the stable oral dosage form, the dosageform comprises 80.34 mg of mannitol, 0.6 mg of aerosil, 10.0 mg ofstarch NF, 20.0 mg of pregelatinized starch, 2.0 mg of stearic acid, 2.0mg of talc, 4.8 mg of hypromellose, 6.25 mg of methacrylic acid ethylacrylate copolymer, 1.25 mg of triethyl citrate, and 3.1 mg of talcextra fine.

In yet another embodiment of the stable oral dosage form, the dosageform comprises 68.3 mg of mannitol, 0.6 mg of aerosil, 10.0 mg of starchNF, 20.0 mg of pregelatinized starch, 2.0 mg of stearic acid, 2.0 mg oftalc, 4.8 mg of hypromellose, 4.0 mg of methacrylic acid ethyl acrylatecopolymer, 0.8 mg of triethyl citrate, and 1.9 mg of talc extra fine.

In yet another embodiment of the stable oral dosage form, the dosageform releases between 80 and 100% of rasagiline when placed in a basketapparatus in 500 mL of buffered aqueous media at a pH of 6.8 at 37° C.at 75 revolutions per minute for 20 minutes.

In yet another embodiment of the stable oral dosage form, the dosageform further comprises rasagline base.

In yet another embodiment of the stable oral dosage form, up to 2% ofthe total amount of rasagiline in the dosage form is present asrasagiline free base.

In yet another embodiment of the stable oral dosage form, the totalamount of non-polar impurities in the dosage form is less than 0.3 wt %relative to the amount of rasagiline.

In yet another embodiment of the stable oral dosage form, the amount ofN-(2-Chloroallyl)-1(R)-aminoindan content in the dosage form is lessthan 20 ppm relative to the amount of rasagiline.

In yet another embodiment of the stable oral dosage form, the amount ofN-(2-Chloroallyl)-1(R)-aminoindan content in the dosage form is lessthan 4 ppm relative to the amount of rasagiline.

In yet another embodiment of the stable oral dosage form, the dosageform when ingested by a human subject achieves MAO-B inhibitionsubstantially the same as that of the corresponding dosage of rasagilineingested as an immediate release formulation.

The subject application provides a method of treating a patientsuffering from Parkinson's disease comprising administering to thepatient the stable oral dosage form.

In an embodiment of the method, the patient suffers from delayed gastricemptying.

By any range disclosed herein, it is meant that all hundredth, tenth andinteger unit amounts within the range are specifically disclosed as partof the invention. Thus, for example, 0.01 mg to 50 mg means that 0.02,0.03 . . . 0.09; 0.1, 0.2 . . . 0.9; and 1, 2 . . . 49 mg unit amountsare included as embodiments of this invention.

Citric acid is a weak organic acid, and is triprotic. Therefore, therasagiline citrate described herein may exist in mono-, di- ortri-rasagiline citrate form or a mixture thereof.

An immediate release formulation of rasagiline is AZILECT® Tablets whichcontain rasagiline (as the mesylate), a propargylamine-based drugindicated for the treatment of idiopathic Parkinson's disease. It isdesignated chemically as 1H-Inden-1-amine, 2, 3-dihydro-N-2-propynyl-,(1R)-, methanesulfonate.

MAO inhibitors that selectively inhibit MAO-B are largely devoid of thepotential to cause the “cheese effect”. Nonetheless, the possibilityexists that delayed gastric emptying of R-PAI may contribute to thisphenomenon. Therefore, a goal in developing the formulations of thecurrent invention was to develop a delayed release, enteric coatedformulation comprising rasagiline in an amount equivalent to 1 mg ofrasagiline base which would release the active ingredient in theduodenum and/or the jejunum, past the stomach.

During the development of the formulations of the current invention, itwas determined that the formulations should meet the criteria ofbioequivalence to the known, immediate release rasagiline mesylateformulations (as disclosed in example 1, for example) in a single dosebio-equivalence study in healthy subjects. These criteria includesimilarity of C_(max) and AUC_(0-t) (area under the curve) within therange of 80-125% within a 90% confidence interval between the newformulations and the known, immediate release formulations. Thedifference between the two formulations should be evident inbioequivalence studies as a difference in t_(max). In other words, themean pharmacokinetic profile of the formulations of the currentinvention should substantially match the mean pharmacokinetic profile ofthe formulations of the known immediate release formulation, with theexception of the t_(max) which should be greater for the delayed releaseformulation than for the immediate release formulation.

The reason for attempting to match the mean C_(max) and AUC_(0-t) of theknown immediate release formulation (i.e. to formulate a delayed releaseformulation that is bioequivalent) is that the efficacy of the immediaterelease formulation has been proven, and it is likely that the efficacyof the formulation relates to its mean C_(max) and/or AUC. (Arch Neurol.2002; 59:1937-1943.)

In order to reach this target, development was directed toward entericcoated tablets having a quickly disintegrating core with an entericcoating which allows release of the rasagiline in a very specific rangeof pH. This specific pH range would prevent the formulation fromreleasing rasagiline in the stomach, and would allow the formulation torelease rasagiline quickly under the physiological conditions of theintestine.

In PCT International Application Publication No. WO 2006/014973, delayedrelease rasagiline mesylate pharmaceutical formulations were disclosed.In the disclosed formulations (Example 1, 2 and 4) methacrylicacid-ethyl acrylate copolymer (1:1) 30% dispersion, known as Eudragit®L-30 D-55 was used. As evident from WO 2006/014973, these formulationswere indeed delayed-release formulations as shown by their dissolutionprofiles and by the in-vivo data, however, their pharmacokineticprofile, in terms of mean C_(max) did not match the pharmacokineticprofile of the immediate release rasagiline mesylate formulations.

The excipient methacrylic acid-ethyl acrylate copolymer (1:1) 30%dispersion, known as Eudragit® L-30 D-55, used in the above-mentionedpublication WO 2006/014973, when applied as an aqueous dispersion eitheron tablets or on spheres prevents dissolution of the coated compositionat low acidic pH. The structure of this polymer is as follows:

The ratio of the free carboxyl groups to the ester groups isapproximately 1:1. The average molecular weight is approximately250,000.

When this excipient is used in an aqueous dispersion or in an organicsolution and formed into a film coating of a pharmaceutical formulation,it is intended to dissolve at a pH of about 5.5. (Aqueous PolymericCoatings for Pharmaceutical Dosage Forms; Second Edition, Revised andExpanded. Ed. James W. McGinity, 1997.) Without wishing to be bound byany theory, it is possible that these prior art formulations began todissolve in lower pH in the stomach, perhaps in the presence of foodwhich can raise the pH in the stomach, and continued to dissolve over aprolonged period of time in the duodenum and the jejunum. It may alsostart releasing after the stomach. The prolonged dissolution periodcould explain why the C_(max) of these prior art formulations wassignificantly lower than the C_(max) of the immediate releaseformulations to which they were compared.

In general, the release process encompasses three major steps:

-   1. Transport to the site where the pH is high enough to initiate    release from the dosage form;-   2. Dissolution of the coating; and-   3. Disintegration and release of the drug from the core.

For highly soluble compounds the third step is the most crucial. Incontrast, for enteric coated pellets for which emptying occursgradually, not all at once, the first step has a major influence on thePK profile. As pellets empty at different times, they reach the secondstep at different time points as well. Therefore the PK profile is asuperimposition of multiple “mini” PK profiles.

The delayed release compositions of the current invention are intendedto withstand pH conditions of 6.0 and are intended to release the activeingredient only above that pH. This specific pH was chosen in order toattempt to minimize any possible dissolution of the pharmaceuticalcompositions of the invention in the stomach in fed condition and toallow rapid dissolution of the pharmaceutical compositions of theinvention after the stomach in the duodenum and/or the jejunum. Theability of a pharmaceutical formulation to enter the duodenum beforereleasing rasagiline and subsequently releasing the rasagiline rapidlyafter the stomach provides a pharmacokinetic profile, and specifically aC_(max) and AUC_(0-t), similar to that of the known immediate releaseformulation.

Achieving the goal of a delayed-release pharmaceutical formulation inwhich the C_(max) is similar to the corresponding immediate-releaseformulation is not trivial to achieve. In general, when delayed releaseformulations are compared to their immediate release counterparts inbio-studies, the C_(max) of the delayed release formulations are lowerthan the C_(max) in the corresponding immediate release formulations.(Marcher, et al. Arneimittelforschung. 2001; 51(6): 465-9. Behr, et al.J. Clin Pharmacol. 2002; 42(7): 791-7.)

In addition, the instant invention provides a solution to the problem ofperipheral MAO inhibition by providing pharmaceutical dosage formscomprising rasagiline which are adapted to inhibit the release orabsorption of rasagiline in the stomach (i.e. delay the release ofrasagiline until at least a portion of the dosage form has traversed thestomach). This avoids or minimizes absorption of rasagiline in thestomach, thereby avoiding or minimizing the potential cheese effect.

The pharmaceutical dosage form may be comprised of an acid resistantexcipient which prevents the dosage form or parts thereof fromcontacting the acidic environment of the stomach. The acid resistantexcipient may coat the rasagiline in the form of an enteric coatedtablet, capsule, hard or soft gelatin capsule. Enteric coating, in thecontext of this invention, is a coating which prevents the dissolutionof an active ingredient in the stomach. This is determined by measuringthe dissolution of the pharmaceutical dosage form in acidic solution, asdefined by USP methods. Even in enteric pharmaceutical dosage forms,some of the dosage form may dissolve in the stomach; however, the dosageform may still be considered enteric according to USP standards.

In all of its aspects, the present invention provides an oralpharmaceutical dosage form useful for treating: Parkinson's disease,brain ischemia, head trauma injury, spinal trauma injury, neurotrauma,neurodegenerative disease, neurotoxic injury, nerve damage, dementia,Alzheimer's type dementia, senile dementia, depression, memorydisorders, hyperactive syndrome, attention deficit disorder, multiplesclerosis, schizophrenia, and/or affective illness, but with a reducedrisk of peripheral MAO inhibition that is typically associated withadministration of rasagiline with known oral dosage forms.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms of the present inventionare described, e.g., in U.S. Pat. No. 6,126,968 to Peskin et al., issuedOct. 3, 2000. Techniques and compositions for making dosage forms usefulin the present invention are described, for example, in the followingreferences: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes,Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al.,1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition(1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack PublishingCompany, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (DavidGanderton, Trevor Jones, Eds., 1992); Advances in PharmaceuticalSciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds.,1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugsand the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers Therapeutic Applications: Drugs andthe Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); DrugDelivery to the Gastrointestinal Tract (Ellis Horwood Books in theBiological Sciences. Series in Pharmaceutical Technology; J. G. Hardy,S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and thePharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T.Rhodes, Eds.).

Tablets may contain suitable binders, lubricants, disintegrating agents,coloring agents, flavoring agents, flow-inducing agents, melting agents,stabilizing agents, solubilizing agents, antioxidants, buffering agent,chelating agents, fillers and plasticizers. For instance, for oraladministration in the dosage unit form of a tablet or capsule, theactive drug component can be combined with an oral, non-toxic,pharmaceutically acceptable, inert carrier such as gelatin, agar,starch, methyl cellulose, dicalcium phosphate, calcium sulfate,mannitol, sorbitol, microcrystalline cellulose and the like. Suitablebinders include starch, gelatin, natural sugars such as corn starch,natural and synthetic gums such as acacia, tragacanth, or sodiumalginate, povidone, carboxymethylcellulose, polyethylene glycol, waxes,and the like. Antioxidants include ascorbic acid, fumaric acid, citricacid, malic acid, gallic acid and its salts and esters, butylatedhydroxyanisole, editic acid. Lubricants used in these dosage formsinclude sodium oleate, sodium stearate, sodium benzoate, sodium acetate,stearic acid, sodium stearyl fumarate, talc and the like. Disintegratorsinclude, without limitation, starch, methyl cellulose, agar, bentonite,xanthan gum, croscarmellose sodium, sodium starch glycolate and thelike, suitable plasticizers include triacetin, triethyl citrate, dibutylsebacate, polyethylene glycol and the like.

The basket-type apparatus used in this invention is the apparatus 1described in the United States Pharmacopeia, 29^(th) Edition (2006),chapter 711. The apparatus is constructed as follows:

The assembly consists of the following: a covered vessel made of glassor other inert, transparent material; a motor; a metallic drive shaft;and a cylindrical basket. The vessel is partially immersed in a suitablewater bath of any convenient size or placed in a heating jacket. Thewater bath or heating jacket permits holding the temperature inside thevessel at 37±0.5 during the test and keeping the bath fluid in constant,smooth motion. No part of the assembly, including the environment inwhich the assembly is placed, contributes significant motion, agitation,or vibration beyond that due to the smoothly rotating stirring element.Apparatus that permits observation of the specimen and stirring elementduring the test is preferable. The vessel is cylindrical, with ahemispherical bottom and with one of the following dimensions andcapacities: for a nominal capacity of 1 L, the height is 160 mm to 210mm and its inside diameter is 98 mm to 106 mm; for a nominal capacity of2 L, the height is 280 mm to 300 mm and its inside diameter is 98 mm to106 mm; and for a nominal capacity of 4 L, the height is 280 mm to 300mm and its inside diameter is 145 mm to 155 mm. Its sides are flanged atthe top. A fitted cover may be used to retard evaporation. The shaft ispositioned so that its axis is not more than 2 mm at any point from thevertical axis of the vessel and rotates smoothly and without significantwobble. A speed-regulating device is used that allows the shaft rotationspeed to be selected and maintained at the rate specified in theindividual monograph, within ±4%. Shaft and basket components of thestirring element are fabricated of stainless steel type 316 orequivalent.

Unless otherwise specified in the individual monograph, use 40-meshcloth. A basket having a gold coating 0.0001 inch (2.5 μm) thick may beused. The dosage unit is placed in a dry basket at the beginning of eachtest. The distance between the inside bottom of the vessel and thebasket is maintained at 25±2 mm during the test.

Due to the sensitivity of rasagiline base to UV radiation and light ingeneral, during the preparation of formulations described in thefollowing examples, it is recommended to perform the process in a low UVradiation environment, preferably in an environment without any UVradiation.

This invention will be better understood from the experimental detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the invention as described more fully in the claims which followthereafter.

Example 1 Rasagiline Immediate Release Tablets

Rasagiline immediate release tablets were prepared using the ingredientslisted in Table 1.

TABLE 1 Per Tablet(mg) Per Tablet(mg) (0.5 mg (1 mg RasagilineRasagiline Component Function base) base) Rasagiline mesylate 0.78 1.56Mannitol Filler 79.62 159.24 Aerosil Flowing 0.6 1.2 Agent Starch NFBinder 10.0 20.0 Starch, Disintegrant 10.0 20.0 Pregelatinized (StarchSTA-RX 1500) Talc Lubricant 2.0 4.0 Stearic Acid Lubricant 2.0 4.0 Totalcore Tablet 105 210 Weight

Rasagiline mesylate, mannitol, half of the colloidal silicon dioxide,starch and pregelatinized starch were mixed in a Diosna P-800 mixer forabout 5 minutes. Water was added and the mixture was mixed further. Thegranulate was dried and the remainder of the colloidal silicon dioxidewas added. The granulate was ground in a Frewitt mill and stearic acidand talc were added. The granulate was mixed for five minutes in atumbler and was tableted.

Example 2 Rasagiline Base Tablet Cores

An attempt was made to formulate tablet cores which would have apharmacokinetic profile (C_(max) and AUC) resembling that of theimmediate release formulation of example 1.

A process for preparing crystalline rasagiline base is disclosed in U.S.Patent Application Publication No. 2008/0161408 (and which correspondssubstantially to WO 2008/076348). In particular, the document describesa process for manufacture of crystalline rasagiline base whichcomprises: a) dissolving a salt of R(+)-N-propargyl-1-aminoindan inwater to form a solution; b) cooling the solution to a temperature ofabout 0-15° C.; c) basifying the solution to a pH of about 11 to form asuspension; and d) obtaining the crystalline rasagiline base from thesuspension.

Five preliminary formulations of rasagiline base as API were preparedusing standard tableting technique based on rasagiline immediate releaseformulation of example 1. Different reagents were added in order tostabilize the API within the formulation.

TABLE 2 Compositions of rasagiline base tablet cores: Composition 1Composition 2 Composition 3 Composition 4 Composition 5 Rasagiline baseRasagiline base Rasagiline base Rasagiline base Rasagiline base CitricAcid Maleic Acid Succinic Acid Malic Acid BHT Mannitol USP/EP MannitolUSP/EP Mannitol USP/EP Mannitol USP/EP Mannitol USP/EP Colloidal SiliconDioxide Colloidal Silicon Dioxide Colloidal Silicon Dioxide ColloidalSilicon Dioxide Colloidal Silicon Dioxide Pregelatinized StarchPregelatinized Starch Pregelatinized Starch Pregelatinized StarchPregelatinized Starch Starch NF/EP Starch NF/EP Starch NF/EP StarchNF/EP Starch NF/EP Stearic Acid Stearic Acid Stearic Acid Stearic AcidStearic Acid Talc Talc Talc Talc Talc

The batches were produced in lab scale of ˜500 tablets using laboratoryequipment with non-GMP lot of API.

Stability results of all five formulations (final mixtures) were put onshort-term stability studies at accelerated and room temperatureconditions. Stability results, content of each formulation anddissolution results of tablets compressed using single punch arepresented in the tables below.

Composition 1 Raw Mg/tab Materials 0.82 Citric Acid Water 1.00Rasagiline base 80.0 Manitol USP/EP 0.3 Aerosil 200 10.0 Starch NF/EP20.0 Starch STA- RX 1500 0.3 Aerosil 200 2.0 Stearic Acid 2.0 Talc116.42 Total weight 2 wks 2 wks 1 mo Time 0 25° C. 40° C. 40° C. Assaystability results (%) 101.6% 94.2% 94.8% 98.0% Stability Results - Levelof Impurity (%) Total <0.04 <0.04 <0.1 <0.2 Impurity (DL) (DL) (QL) (QL)

Composition 2 Raw Mg/tab Materials 0.7 Maleic Acid Water 1.00 Rasagilinebase 80.0 Manitol USP/EP 0.3 Aerosil 200 10.0 Starch NF/EP 20.0 StarchSTA-RX 1500 0.3 Aerosil 200 2.0 Stearic Acid 2.0 Talc 116.3 Total weight2 wks 2 wks 1 mo Time 0 25° C. 40° C. 40° C. Assay stability results (%)82.3 84.6 79.8 80.8 Stability Results - Level of Impurity (%) Total <0.10.1 0.4 0.8 Impurity (QL)

Composition 3 Mg/ Raw tab Materials 0.7 Succinic Acid Water 1.00Rasagiline base 80.0 Manitol USP/EP 0.3 Aerosil 200 10.0 Starch NF/EP20.0 Starch STA-RX 1500 0.3 Aerosil 200 2.0 Stearic Acid 2.0 Talc 116.3Total weight Time 0 2 wks 25° C. 2 wks 40° C. 1 mo 40° C. Assaystability results (%) 102.9 99.4 100.6 101.9 Stability Results - Levelof Impurity (%) Total 0.4 0.4 0.6 1.2 Impurity

Composition 4 Raw Mg/tab Materials 0.8 Malic Acid Water 1.00 Rasagilinebase 80.0 Manitol USP/EP 0.3 Aerosil 200 10.0 Starch NF/EP 20.0 StarchSTA-RX 1500 0.3 Aerosil 200 2.0 Stearic Acid 2.0 Talc 116.4 Total weight2 wks 2 wks 1 mo Time 0 25° C. 40° C. 40° C. Assay stability results (%)103.4 101.5 101.5 102.2 Stability Results - Level of Impurity (%) Total<0.04 <0.04 <0.1 <0.2 Impurity (DL) (DL) (QL) (QL)

Composition 5 Mg/ Raw tab Materials Ethanol 95% 0.02 BHT 1.00 Rasagilinebase 80.0 Manitol USP/EP 0.3 Aerosil 200 10.0 Starch NF/EP 20.0 StarchSTA-RX 1500 0.3 Aerosil 200 2.0 Stearic Acid 2.0 Talc 115.62 Totalweight 2 wks 2 wks 1 mo Time 0 25° C. 40° C. 40° C. Assay stabilityresults (%) 67.8 65.7 48.5 31.9 Stability Results - Level of Impurity(%) Total <0.1 <0.1 2.9 5.7 Impurity (QL) (QL)

Dissolution Results (% in 0.1N HCl)

5 min 10 min 15 min Composition 1 85 99 100 Composition 2 49 82 90Composition 3 62 98 103 Composition 4 59 100 107 Composition 5 70 70 70Dissolution Results (% in Phosphate buffer pH 6.8)

5 min 10 min 15 min Composition 1 78 92 94 Composition 2 40 77 82Composition 3 59 98 101 Composition 4 59 95 102 Composition 5 70 70 70

Discussion:

Compositions 1 and 4, which contain antioxidants Citric and Malic acidsrespectively, gave the best stability results and satisfactorydissolution profile. Therefore, they were chosen for future development.

Example 3a Preparation of Rasagiline Base Delayed Release Enteric CoatedTablet—Formulation I

In this example, a 1 mg rasagiline base delayed release enteric coatedtablet containing citric acid (117 mg core tablet weight) was prepared.

TABLE 3a Composition of rasagiline base delayed release enteric coatedtablet Per Tablet Component Function (mg) Core tablets Rasagiline BaseDrug Substance 1.0 Citric Acid Antioxidant/Stabilizer 1.6 MannitolFiller 79.84 Colloidal Silicon Flowing Agent 0.6 Dioxide Starch NFBinder 10.0 Starch, Pregelatinized Disintegrant 20.0 (STA-RX ® 1500)Talc Lubricant 2.0 Stearic Acid Lubricant 2.0 Total Core Tablet 117.0Weight Subcoating Pharmacoat ® 606 Coating Agent 4.8 (Hypromellose USP)Granules Purified Water Processing Agent Coating Suspension Eudragit ®L-30D-55 Coating Agent 6.250* Talc USP Extra Fine Lubricant 1.25Triethyl citrate Plasticizer 3.1 Purified Water Processing Agent TotalTablet Weight 132.4 *Dry substance remaining on the core.

I. Dry Mixing:

Mannitol, half amount of Aerosil, Pregelatinized Starch and Starch NFwere placed in a high shear granulating mixer and were premixed for 1minute mixing at mixer speed I, followed by 1 minute mixing at mixerspeed I and chopper I.

II. Wet Granulation:

Citric acid solution was prepared using 320 g of citric acid, inpurified water in a weight ratio of approximately 1:10.6 to 1:6.

Rasagiline Base was added with stirring for approximately 15 minutes.The stirring was continued until a clear solution was observed. Thesolution was added into a high shear granulating mixer and the contentwas mixed for approximately 2 minutes at mixer speed II and chopper II.An extra amount of water was added into the high shear granulatingmixer, and the solution was mixed for two more minutes at mixer speed IIand chopper II.

The wet granulate was discharged into a fluid bed dryer trolley at mixerspeed I.

III. Fluid Bed Drying:

The material from step II was dried in a fluid bed dryer under inlet airtemperature of 45° C. (40° to 50° C.) and outlet air temperature ofmaximum 37-38° C.

IV. Milling:

The dry granulate and the residual amount of Aerosil were milled throughan oscillating granulator with screen 0.6 mm into a storage container.

The milled granulate was further weighted.

V. Final Blending:

Stearic Acid and Talc were sieved through a 50 mesh screen and weretransferred to the Y-cone/Bin.

-   1. The mixture was mixed for 5 minutes.-   2. The Final Blend and the percentage yield were determined.-   3. The final blend was stored in a container using an inner    transparent polyethylene bag and an outer black polyethylene bag.    Two Silica gel pillows were placed between the two polyethylene    bags.-   4. Samples were taken for a Blend Uniformity test.

VI. Tablet Compression:

A tablet compression machine (FETTE 1200) was set up with the designatedpunches 6.0 mm.

The in-process control testing for tablets included average weight,individual weight, thickness, hardness, friability and disintegration.

In process control specifications for Rasagiline Base DR 1 mg tabletsis:

Parameter Minimum Target Maximum Average weight (mg) 111 117 123Individual weight (mg) 111 117 123 Thickness (mm) 3.3 3.6 3.9 Hardness(SCU) 7 9 11 Friability (%) — — 1.0 Disintegration — — 5 (minutes)

The tablets were weighted and the percentage yield was calculated.

VII. Sub-Coating:

Tablet cores were first coated with hypromellose (Pharmacoat 606®) as apre-coating, followed by coating with Methacrylic Acid-MethylMethacrylate Copolymer [1:1] (30% dispersion of Eudragit® L100-55) toprevent any possible interaction between the Rasagiline base in the coreand the Eudragit L polymer.

1. Preparation of Pharmacoat 606® Solution:

-   -   Hypromellose USP solution was prepared using hypromellose, in        purified water in a weight ratio of approximately 1:10.

2. Pre Heating:

-   -   The tablet cores were placed in an (Ohara) Coater coating pan.        The tablets were heated under inlet air temperature of 50° C.        (45° to 55° C.) and outlet air temperature of 45-50° C.

3. Spraying Process:

-   -   The tablet cores were sprayed with hypromellose solution in the        Ohara Coater coating pan. The inlet air temperature was 50° C.;        the outlet air temperature was 35° C. The pan speed was set to        16 rpm (can vary from 14 to 18 rpm). Spraying rate was 15-35        gr/min. The tablets were dried for 1 hour with inlet air        temperature of 45° C. (temperature range is 40° C.-50° C.).

VIII. Enteric Coating: 1. Preparation of Enteric Coating Dispersion ofEudragit® L100-55:

-   -   Triethyl citrate was mixed with water for 15 minutes. The Talc        Extra fine was added into the Triethyl citrate and water        dispersion in an Ultraturax within 10 minutes. Eudragit L100-55        30% dispersion was added to Triethyl citrate/talc dispersion,        filtered and stirred.

2. Pre Heating:

-   -   The precoated tablets were placed in an Ohara Coater coating        pan. The tablets were heated under inlet air temperature of        50° C. (45° to 55° C.) and outlet air temperature of 45° C. (40°        to 50° C.)

3. Spraying Process:

-   -   The tablets were sprayed with the dispersion in an Ohara coater        pan. The inlet air temperature was in the range of 40° C.-50 the        outlet air temperature was in the range of 30-40° C. The pan        speed was set to 16 rpm in range of 14-18 rpm, and the spraying        rate was 5-20 gr/min. The tablets were dried for 2 hours. The        inlet air temperature was 50° C. on minimum pan speed.

EUDRAGIT® L 100-55 contains an anionic copolymer based on methacrylicacid and ethyl acrylate. It is also known as methacrylic acid copolymer,type C. The ratio of the free carboxyl groups to the ester groups isapprox. 1:1. The average molecular weight is approx. 250,000.

Example 3b Preparation of 1 mg Rasagiline Base Delayed Release EntericCoated Tablet—Formulation III

In this example, a 1 mg rasagiline base delayed release enteric coatedtablet containing citric acid (76 mg core tablet weight) was preparedusing similar steps as described in example 3a.

TABLE 3b composition of rasagiline-base delayed release enteric coatedtablet Per Tablet Component Function (mg) Core tablets Rasagiline baseDrug Substance 1.0 Citric acid Antioxidant/ 1.6 Stabilizer MannitolFiller 45.0 Aerosil Flowing Agent 0.4 Starch NF Binder 5.0 Starch,Pregelatinized Disintegrant 20.0 (Starch STA-RX 1500) Talc Lubricant 1.5Stearic Acid Lubricant 1.5 Total Core Tablet 76.0 Weight SubcoatingPharmacoat ® 606 Coating Agent 3.5 (Hypromellose USP) Granules PurifiedWater Processing Agent Coating Suspension Eudragit ® L-30D-55 CoatingAgent 4.0* Talc USP Extra Fine Lubricant 1.9 Triethyl citrate NFPlasticizer 0.8 Purified Water Processing Agent Total Tablet Weight 86.2*Dry substance remaining on the core.

Example 3c Preparation of 0.5 mg Rasagiline Base Delayed Release EntericCoated Tablet

In this example, a 0.5 mg rasagiline base delayed release enteric coatedtablet containing citric acid (117 mg core tablet weight) was preparedusing similar steps as described in example 3a.

TABLE 3c composition of rasagiline-base delayed release enteric coatedtablet Per Tablet Component Function (mg) Core tablets Rasagiline baseDrug Substance 0.5 Citric acid Antioxidant/ 1.6 Stabilizer MannitolFiller 80.34 Aerosil Flowing Agent 0.6 Starch NF Binder 10.0 Starch,Pregelatinized Disintegrant 20.0 (Starch STA-RX 1500) Talc Lubricant 2.0Stearic Acid Lubricant 2.0 Total Core Tablet 117.0 Weight SubcoatingPharmacoat ® 606 Coating Agent 4.8 (Hypromellose USP) Granules PurifiedWater Processing Agent Coating Suspension Eudragit ® L-30D-55 CoatingAgent 6.25* Talc USP Extra Fine Lubricant 3.1 Triethyl citrate NFPlasticizer 1.25 Purified Water Processing Agent Total Tablet weight132.4 *Dry substance remaining on the core.

Example 3d Preparation of 0.5 mg Rasagiline Base Delayed Release EntericCoated Tablet

In this example, a 0.5 mg rasagiline base delayed release enteric coatedtablet containing citric acid (76 mg core tablet weight) was preparedusing similar steps as described in example 3a.

TABLE 3d composition of rasagiline-base delayed release enteric coatedtablet Per Tablet Component Function (mg) Core tablets Rasagiline baseDrug Substance 0.5 Citric acid Antioxidant/ 1.6 Stabilizer MannitolFiller 45.5 Aerosil Flowing Agent 0.4 Starch NF Binder 5.0 Starch,Pregelatinized Disintegrant 20.0 (Starch STA-RX 1500) Talc Lubricant 1.5Stearic Acid Lubricant 1.5 Total Core Tablet 76.0 Weight SubcoatingPharmacoat ® 606 Coating Agent 3.5 (Hypromellose USP) Granules PurifiedWater Processing Agent Coating Suspension Eudragit ® L-30D-55 CoatingAgent 4.0* Talc USP Extra Fine Lubricant 1.9 Triethyl citrate NFPlasticizer 0.8 Purified Water Processing Agent Total Tablet Weight 86.2*Dry substance remaining on the core.

Example 4 Dissolution Results of Tablets Prepared According to Example3a

The tablets prepared according to example 3a were tested for dissolutionprofile in various media according to USP procedures. The data belowrepresents average for 4 tablets.

The % rasagiline released in the following tables is relative to astandard which is 1 mg rasagiline.

Tablet Cores:

Dissolution Profile (% Rasagiline Released)—0.1N HCl, 75 rpm, 37° C.

10 min 20 min 30 min 45 min 1 101 102 102 103 2 105 106 105 106 3 104105 105 105 4 106 106 107 107 % Mean 104 105 105 105Dissolution Profile (% Rasagiline Released)—Phosphate Buffer, 75 rpm,37° C.

10 min 20 min 30 min 45 min 1 98 99 99 99 2 100 101 101 102 3 99 100 100101 4 96 96 97 97 % Mean 98 99 99 100 % RSD 1.9 2.0 2.0 2.2

Sub-Coated Tablets:

Dissolution Profile (% Rasagiline Released)—0.1N HCl, 75 rpm, 37° C.

10 min 20 min 30 min 45 min 1 105 105 106 106 2 109 109 109 109 3 103104 104 104 4 103 104 103 104 % Mean 105 105 105 106 % RSD 2.5 2.3 2.32.3

Coated Tablets:

The dissolution profile of the coated tablets in 0.1N HCl was acceptableaccording to USP specification for delayed release (enteric coated)articles, 29th edition, Chapter 724, showing less than 10% release after120 minutes.

Dissolution Profile (% Rasagiline Released)—Phosphate Buffer pH 5.8

10 min 20 min 30 min 40 min 60 min 90 min % Mean 0 0 0 0 0

Dissolution Profile (% Rasagiline Released)—Phosphate Buffer pH 6.4

10 min 20 min 30 min 40 min 60 min 90 min % Mean 0 35 93 96 96 96 % RSD2.2 1.3 1.3 1.2

Dissolution Profile (% Rasagiline Released)—Phosphate Buffer pH 6.8

10 min 20 min 30 min 40 min 60 min 90 min % Mean 11 92 95 95 94 94 % RSD3.7 1.6 1.6 1.5 1.6

Discussion:

The tablets prepared according to Example 3a do not begin the release ofrasagiline at a pH lower than 6.0. At a pH of 6.8, there is a rapidrelease of rasagiline and within approximately 20 minutes, above 90% ofthe rasagiline is released from the formulation.

During the development of the formulations of the current invention, itwas determined that the formulations should meet the criteria ofbioequivalence to the known, immediate release rasagiline mesylateformulations (as disclosed in example 1) in a single dosebio-equivalence study in healthy subjects. These criteria includesimilarity of C_(max) and/or AUC_(0-t) (area under the curve) within therange of 80-125% within a 90% confidence interval between the newformulations and the known, immediate release formulations. Thedifference between the two formulations should be evident inbioequivalence studies as a difference in t_(max). In other words, themean pharmacokinetic profile of the formulations of the currentinvention should match substantially the mean pharmacokinetic profile ofthe formulations of the immediate release formulation, with theexception of the t_(max) which should be greater for the delayed releaseformulation than for the immediate release formulation.

The reason for attempting to match the mean C_(max) and AUC_(0-t) of theknown immediate release formulation (i.e. to formulate a delayed releaseformulation that is bioequivalent) is that the efficacy of the immediaterelease formulation has been proven, and it is likely that the efficacyof the formulation relates to its mean C_(max) and/or AUC. (Arch Neurol.2002; 59:1937-1943.)

In order to reach this target, development was directed toward delayedrelease enteric coated tablets having a quickly disintegrating core withan enteric coating which allows release of the rasagiline in a veryspecific range of pH. This specific pH range would prevent theformulation to release rasagiline in the stomach in fed condition, andwould allow the formulation to release rasagiline quickly under thephysiological conditions of the intestine after the stomach.

Although the tablets of example 3a were coated with an enteric coatingcomprising Methacrylic Acid Ethyl Acrylate copolymer, as were thecompositions in PCT application publication WO 2006/014973, the tabletsaccording to example 3a were capable of withstanding pH of 6.0 andbelow, whereas the composition in WO 2006/014973 were not.

The difference in dissolution profiles stems from the fact that thecore's formulation contained high amount of disintegrant and the entericfilm has a lower ratio of polymer to plasticizer is used in thecompositions of the invention. The ratio of polymer to plasticizerbetween 10:1 and 2:1, and specifically 5:1, allows for enhanced in vitrodissolution profiles.

The dissolution profile of the formulation of Example 3a allows thecomposition to have enhanced pharmacokinetic properties, similar to thecurrently marketed immediate release formulations.

Example 5 Stability Results of Tablets Prepared According to Example 3a

Stability of enteric coated tablets produced using formulationscontaining citric acid was tested under different storage conditions.The results are summarized below.

Stability Results (Accelerated Conditions):

The dissolution profile of the enteric coated tablets in 0.1N HCl wasacceptable according to USP specification for delayed release (entericcoated) articles, 29th edition, Chapter 724, showing less than 10%release after 120 minutes.

The following table shows that dissolution profile for enteric coatedtablets after different period of storage.

Dissolution Profile of Coated Tablets—Phosphate Buffer pH 6.8, 37° C.

Storage Dissolution Profile after Different Period Period of Storage (%rasagiline released) (months) 10 min 20 min 30 min 40 min 60 min 90 min0 11 92 95 95 96 96 1 28 95 96 96 97 97 2 12 97 98 98 98 99 3 35 101 103103 104 104

The % rasagiline released in the above table is relative to a standardwhich is 1 mg rasagiline.

The following tables show that analytical results for different batchesof the enteric coated tablets under various storage conditions.

Coated Tablets—Batch 1

Conditions Assay % Total Impurities (%) T = 0 101.5 <DL 40° C., 75 RH 1Mo 101.1 <DL 2 Mo 105.4 0.3% 3 Mo 104.5 0.4% 4 Mo 100.9 0.4% 25° C., 60RH 1 Mo 104.7 <DL 3 Mo 106.2 <DL

Coated Tablets—Batch 2

Conditions Assay % Total Impurities (%) T = 0 98.6 <DL 40° C., 75 RH 1Mo 99.1 0.05% 2 Mo 96.3 0.1% 3 Mo 95.6 0.2% 4 Mo 96.6 0.3% 30° C., 65 RH1 Mo 99.8 <DL 2 Mo 98.4 <DL 3 Mo 96.5 <DL 25° C., 60 RH 1 Mo 98.4 <DL 2Mo 95.8 <DL 3 Mo 96.2 <DL

Coated Tablets—Batch 3

Conditions Assay % Total Impurities (%) T = 0 100.3 <DL 40° C., 75 RH 1Mo 100.3 <DL 40° C., 75 RH 2 Mo 102.0 <DL 40° C., 75 RH 3 Mo <0.28 30°C., 65 RH 3 Mo <0.08 25° C., 60 RH 1 Mo 101.2 <DL 25° C., 60 RH 2 Mo102.1 <DL 25° C., 60 RH 3 Mo <0.08

N-(2-Chloroallyl)-1(R)-Aminoindan (2-Cl-AAI) Impurities

Batch No. 2-Cl-AAI Content, % 1 LT 0.00004 2 LT 0.00004

Example 6a Preparation of Rasagiline Base Delayed Release Enteric CoatedTablets

In this example, a 1 mg rasagiline base delayed release enteric coatedtablet containing malic acid (117 mg core tablet weight) was prepared.

TABLE 4a composition of rasagiline-base delayed release enteric coatedtablet Per Tablet Component Function (mg) Core tablets Rasagiline baseDrug Substance 1.0 Malic acid Antioxidant/ 1.6 Stabilizer MannitolFiller 80.0 Aerosil Flowing Agent 0.6 Starch NF Binder 10.0 Starch,Pregelatinized Disintegrant 20.0 (Starch STA-RX ® 1500) Talc Lubricant2.0 Stearic Acid Lubricant 2.0 Total Core Tablet 117.2 Weight SubcoatingPharmacoat ® 606 Coating Agent 4.8 (Hypromellose USP) Granules PurifiedWater Processing Agent Coating Suspention Eudragit ® L-30D-55 CoatingAgent 6.25* Talc USP Extra Fine Lubricant 3.1 Triethyl citrate NFPlasticizer 1.25 Purified Water Processing Agent Total Tablet Weight132.6 *Dry substance remaining on the core.

I. Dry Mixing:

Mannitol, half amount of Aerosil, Starch Pregelatinized and starch NFare placed into a high shear granulating mixer and are premixed for 1minute mixing at mixer speed I, followed by 1 minute mixing at mixerspeed II and chopper II.

II. Wet Granulation:

Malic acid solution was prepared using malic acid in purified water inthe ratio of approximately 1:10.6 to 1:6.

Rasagiline Base was added with stirring for approximately 15 minutes.The stirring was continued until a clear solution was observed.

The solution was added into a high shear granulating mixer and was mixedfor approximately 2 minute mixing at mixer speed II and chopper II. Anextra amount of water was added into the high shear granulating mixer,and the solution was mixed for two more minutes at mixer speed II andchopper II.

The wet granulate was discharged to a fluid bed dryer trolley at mixerspeed I.

III. Fluid Bed Drying:

The material was dried in a fluid bed dryer under inlet air temperatureof 45° C. (40° to 50° C.) and outlet air temperature of maximum 37-38°C.

IV. Milling:

The dry granulate was milled with the residual amount of Aerosil throughan oscillating granulator with screen 0.6 mm into storage container.

The milled granulate is weighed.

V. Final Blending:

1. Stearic Acid and Talc were sieved through a 50 mesh screen andtransferred to the Y-cone or Bin.2. The mixture was mixed for 5 minutes.3. The final blend was stored in a container using an inner transparentpolyethylene bag and an outer black polyethylene bag. Two Silica gelpillows were placed between the two polyethylene bags.4. Samples were taken for a Blend Uniformity test.

VI. Tablet Compression:

The compressing tablet machine was set up with the designated punches6.0 mm. The diameter of the punch may change +/−10%.

The in-process control testing for tablets includes average weight,individual weight, thickness, hardness, friability and disintegration.

In process control specifications for the Rasagiline Base DR 1 mg tabletcores are:

Parameter Minimum Target Maximum Avarage weight 111 117 (121 Actual) 123(mg) Individual weight 111 117 123 (mg) Tickness (mm) 3.3 3.6 (3.7Actual) 3.9 Hardness (SCU) 7 9 (10 Actual) 11 Friability (%) — — 1.0Disintegration — — 5 (minutes)

The tablet cores are weighed and the percentage yield is calculated.

VII. Sub-Coating:

Tablet cores were first coated with hypromellose (Pharmacoat 606) as apre-coating, followed by Methacrylic Acid-Methyl Methacrylate Copolymer[1:1] (30% dispersion of Eudragit® L100-55) to prevent any possibleinteraction between the Rasagiline base in the core and the Eudragit Lpolymer.

1. Preparation of Pharmacoat 606 Solution:

-   -   Pharmacoat 606 (hypromellose USP) solution was prepared using        Pharmacoat 606 in purified water in a weight ratio of 1:10.

2. Pre Heating:

-   -   The tablet cores are place in an Ohara Coater coating pan the        tablets was heated under inlet air temperature of 50° C. (45° to        55° C.) and outlet air temperature of 40° to 50° C.

3. Spraying Process:

-   -   The tablet cores were sprayed with solution in an

Ohara Coater coating pan. The inlet air temperature was 50° C. (in therange of 40-50° C.); the outlet air temperature was in range of 30-40°C. The pan speed was set to 16 rpm in the range of 14-18 rpm; sprayingrate was 15-35 gr/min. The tablets were dried for 1 hour with inlet airtemperature of 45° C. (in the range of 40-50° C.)

VIII. Enteric Coating:

The Rasagiline subcoated drug product tablet formulation described inprevious section was used for the enteric coated.

1. Preparation of Eudragit® L100-55 Dispersion:

-   -   Triethyl citrate was mixed with the water for 15 min. The Talc        Extra fine was added into the Triethyl citrate and water        dispersion in an Ultraturax within 10 minutes.    -   Eudragit® L100-55 was added to Triethyl citrate/talc dispersion,        filtered and stirred to the continuation of the process.

2. Pre Heating:

-   -   The tablet cores are place in an Ohara Coater coating pan the        tablets was heated under inlet air temperature of 50° C. (45° to        55° C.) and outlet air temperature of 45° C. (40° to 50° C.)

2. Spraying Process:

-   -   The tablets were sprayed with the dispersion in an Ohara coater        pan. The inlet air temperature was 45° C.; the outlet air        temperature was 35° C. (in range of 30-40° C.). The pan speed        was set to 16 rpm (in the range of 14-18 rpm), and the spraying        rate was 5-20 gr/min. The tablets were dried for 2 hours; with        inlet air temperature of 50° C. (in the range of 45-55° C.), on        minimum pan speed.

Example 6b Preparation of 1 mg Rasagiline Base Delayed Release EntericCoated Tablet

In this example, a 1 mg rasagiline base delayed release enteric coatedtablet containing malic acid (76 mg core tablet weight) was preparedusing similar steps as described in example 6a.

TABLE 4b composition of rasagiline-base delayed release enteric coatedtablet Per Tablet Component Function (mg) Core tablets Rasagiline baseDrug Substance 1.0 Malic acid Antioxidant/ 1.6 Stabilizer MannitolFiller 45.0 Aerosil Flowing Agent 0.4 Starch NF Binder 5.0 Starch,Pregelatinized Disintegrant 20.0 (Starch STA-RX 1500) Talc Lubricant 1.5Stearic Acid Lubricant 1.5 Total Core Tablet 76.0 Weight SubcoatingPharmacoat ® 606 Coating Agent 3.5 (Hypromellose USP) Granules PurifiedWater Processing Agent Coating Suspension Eudragit ® L-30D-55 CoatingAgent 4.0* Talc USP Extra Fine Lubricant 1.9 Triethyl citrate NFPlasticizer 0.8 Purified Water Processing Agent Total Tablet weight 86.2*Dry substance remaining on the core.

Example 6c Preparation of 0.5 mg Rasagiline Base Delayed Release EntericCoated Tablet

In this example, a 0.5 mg rasagiline base delayed release enteric coatedtablet containing malic acid (117 mg core tablet weight) was preparedusing similar steps as described in example 6a.

TABLE 4c composition of rasagiline-base delayed release enteric coatedtablet Per Tablet Component Function (mg) Core tablets Rasagiline baseDrug Substance 0.5 Malic acid Antioxidant/ 1.6 Stabilizer MannitolFiller 80.34 Aerosil Flowing Agent 0.6 Starch NF Binder 10.0 Starch,Pregelatinized Disintegrant 20.0 (Starch STA-RX 1500) Talc Lubricant 2.0Stearic Acid Lubricant 2.0 Total Core Tablet 117.0 Weight SubcoatingPharmacoat ® 606 Coating Agent 4.8 (Hypromellose USP) Granules PurifiedWater Processing Agent Coating Suspension Eudragit ® L-30D-55 CoatingAgent 6.25* Talc USP Extra Fine Lubricant 3.1 Triethyl citrate NFPlasticizer 1.25 Purified Water Processing Agent Total Tablet Weight132.4 *Dry substance remaining on the core.

Example 6d Preparation of 0.5 mg Rasagiline Base Delayed Release EntericCoated Tablet

In this example, a 0.5 mg rasagiline base delayed release enteric coatedtablet containing malic acid (76 mg core tablet weight) was preparedusing similar steps as described in example 6a.

TABLE 4d composition of rasagiline-base delayed release enteric coatedtablet Per Tablet Component Function (mg) Core tablets Rasagiline baseDrug Substance 0.5 Malic acid Antioxidant/ 1.6 Stabilizer MannitolFiller 45.5 Aerosil Flowing Agent 0.4 Starch NF Binder 5.0 Starch,Pregelatinized Disintegrant 20.0 (Starch STA-RX 1500) Talc Lubricant 1.5Stearic Acid Lubricant 1.5 Total Core Tablet 76.0 Weight SubcoatingPharmacoat ® 606 Coating Agent 3.5 (Hypromellose USP) Granules PurifiedWater Processing Agent Coating Suspension Eudragit ® L-30D-55 CoatingAgent 4.0* Talc USP Extra Fine Lubricant 1.9 Triethyl citrate NFPlasticizer 0.8 Purified Water Processing Agent Total Tablet weight 86.2*Dry substance remaining on the core.

Example 7 Dissolution Results of Tablets According to Example 6a

The tablets prepared according to example 6a were tested for dissolutionprofile in various media according to USP procedures. The data belowrepresents the average for 4 tablets.

The dissolution profile of the enteric coated tablets in 0.1N HCl wasacceptable according to USP specification for delayed release (entericcoated) articles, 29th edition, Chapter 724, showing less than 10%release after 120 minutes.

Example 8 Stability Results of Tablets Prepared According to Example 6a

Stability of enteric coated tablets produced using formulationscontaining citric acid was tested under different storage conditions.The results are summarized below.

Stability Results (Accelerated Conditions):

The dissolution profile of the enteric coated tablets in 0.1N HCl wasacceptable according to USP specification for delayed release (entericcoated) articles, 29th edition, Chapter 724, showing less than 10%release after 120 minutes.

The following table shows that dissolution profile for enteric coatedtablets after different period of storage.

Dissolution Profile of Coated Tablets—Phosphate Buffer pH 6.8, 37° C.

Storage Dissolution Profile after Different Period Period of Storage (%rasagiline released) (months) 10 min 20 min 30 min 40 min 60 min 90 min1 0 89 93 94 94 94 2 0 92 93 93 94 94

The % rasagiline released in the above table is relative to a standardwhich is 1 mg rasagiline.

The following tables show that analytical results for tablets undervarious storage conditions.

Tablet Cores:

Conditions Assay (%) Total Impurities T = 0 101.2 <DL 1 Mo 101.1 0.1 40°C., 75 RH 2 Mo 98.3 0.3 3 Mo 93.3 0.5 4 Mo 93.1 0.4 1 Mo 101.4 <DL 30°C., 65 RH 2 Mo 101.9 <QL 3 Mo 98.3 <QL 1 Mo 101.5 <DL 25° C., 60 RH 2 Mo102.0 <QL 3 Mo 100.3 <QL

Enteric Coated Tablets:

Conditions Assay % Total Impurities T = 0 98.2 <QL 1 Mo 100.5 0.2 40°C., 75 RH 2 Mo 96.4 0.3 3 Mo 96.6 0.5 1 Mo 98.2 <QL 30° C., 65 RH 2 Mo100.2 <QL 3 Mo 101.0 0.1 1 Mo 101.5 <QL 25° C., 60 RH 2 Mo 96.7 <QL 3 Mo99.5 <QL

N-(2-Chloroallyl)-1(R)-Aminoindan (2-Cl-AAI) Impurities

Batch No 2-Cl-AAI Content, % 1 <0.00004

Example 9 Preparation of Rasagiline Base Tablet Cores (with Citric Acid)

Raw material mg/tablet Percentage Part I, Granulation solution Citricacid 1.6 2.0 Rasagiline base 1 1.25 Purified Water 12.35 15.44 Part IIMannitol 48.5 60.63 Aerosil 200 0.18 0.22 Starch NF/BP 6.1 7.62Pregelatinized starch 20.0 25.0 NF/Ph. Eur Part III Aerosil 200 0.180.22 Part IV Stearic acid 1.22 1.52 Talc 1.22 1.52 Total: 80.0 100

The above composition can also be used to prepare rasagiline basetablets with malic acid by replacing the citric acid with the sameamount of malic acid.

Calculated amounts of external excipients in accordance with actualamount of granulate:

mg/tablet Raw material Percentage Part III Granulate 0.18 Aerosil 2000.22 Part IV 1.22 Stearic acid 1.52 1.22 Talc 1.52

I. Granulation Solution Preparation:

-   1. Weigh 80% of needed amount of Purified water into glass.-   2. Weigh into the same glass Citric acid.-   3. Insert stirrer into the glass and start to stir up to complete    solubility about 5-10 minutes.-   4. Weigh Rasagiline base and add it into the obtained Citric acid    solution.-   5. Continue stirring about 30 minutes to complete solubility of API.

II. Granulation Preparation:

-   1. Weigh Mannitol, Aerosil 200, Starch and Pregelatinized starch and    transfer all excipients to Diosna P-6 (Diosna) and mix for 1 minute    with Mixer I (270 rpm).-   2. Mix the excipient for 1 addition minute with Mixer I (270 rpm)    and Chopper I (1500 rpm)-   3. Add Granulation solution into the Diosna P-6 (Diosna) and mix for    2 minutes with Mixer II (540 rpm) and Chopper II (2200 rpm).-   4. Clean glass after granulation solution with 46.563 g of Purified    water and add it into the Diosna P-6 (Diosna).-   5. Mix for 2 minutes with Mixer II (540 rpm) and Chopper II (2200    rpm).-   6. Transfer obtained granulate into the Glatt 1.1 (Fluid Bed) for    drying at 37° C. inlet air up to L.O.D. NMT 1.5%.

Conditions of Drying: Inlet: Min.—35° C.; Target—50° C.; Max.—55° C.

Outet: Product temperature—37° C.

Flow: Min.—25; Target—60; Max.—1000 III. Milling:

Mill granulate through 0.6 mm sieve using Frewitt.

IV. Final Blend:

-   1. Weigh obtained amount of granulate.-   2. Calculate amounts of Aerosil 200, Stearic acid and Talc in    accordance with actual granulation weight.-   3. Screen Aerosil 200 through 50 mesh sieve.-   4. Weigh needed amount of Aerosil 200 after sieving.-   5. Transfer milled granulate and Aerosil 200 after sieving into the    Y-cone.-   6. Mix for 2 minutes.-   7. Weigh Stearic acid and Talc.-   8. Screen these excipients through 50 mesh sieve.-   9. Transfer them into the Y-cone.-   10. Mix for 5 minutes.

V. Tablet Compression: Machine: Sviac

Diameter of punch: 5.0 mm (it may be changed ±10%)Tablet weight—80 mg±5%

Hardness: 3-7 kP Friability: Not More Than 1%

Disintegration: Not More Than 5 minutes

Example 10 Preparation of Rasagiline Base Tablet Cores (with Malic Acid)

mg/ Raw material tablet Percentage Part I, Granulation solution Malicacid 1.6 3.72 Rasagiline base 1 2.33 Part II Mannitol 25.8 60.0 Aerosil200 0.1 0.24 Starch NF/BP 3.0 6.98 Pregelatinized starch NF/Ph. Eur 10.023.26 Part III Aerosil 200 0.1 0.23 Part IV Stearic acid 0.7 1.63 Talc0.7 1.63 Total: 43.0 100

The above composition can also be used to prepare rasagiline basetablets with citric acid by replacing the malic acid with the sameamount of citric acid.

I. Granulation Solution Preparation.

-   -   1. Weigh 80% of needed amount of Purified water into glass.    -   2. Weigh Malic acid and add it into the same glass.    -   3. Insert stirrer into the glass and start to stir up to        complete solubility about 5-10 minutes.    -   4. Weigh Rasagiline base and add it into the obtained Malic acid        solution.    -   5. Continue stirring about 30 minutes to complete solubility of        API.

II. Granulation Preparation.

-   -   1. Weigh Mannitol, Aerosil 200, Starch and Pregelatinized starch        and transfer all excipients to Diosna P-10 (Diosna) and mix for        1 minute with Mixer I.    -   2. Mix the excipient for 1 addition minute with Mixer I and        Chopper I rpm.    -   3. Add granulation solution into the Diosna P-10 (Diosna) and        mix for 2 minutes with Mixer II and Chopper II.    -   4. Add additional Purified Water into the Diosna P-10 (Diosna)        and mix for 2 minutes with Mixer II, and Chopper II.    -   5. Transfer obtained granulate into the Glatt 5 (Fluid Bed) for        drying at 37° C. inlet air up to L.O.D. NMT 1.5%.

Conditions of Drying: Inlet: Min.—35° C.; Target—50° C.; Max.—55° C.

Outet: Product temperature—37° C.

III. Milling.

Weigh and add Aerosil 200 to granulate and milled granulate through 0.6mm sieve using Frewitt.

IV. Final Blend.

-   1. Weigh Stearic acid and Talc.-   2. Screen the excipients through 50 mesh sieve.-   3. Transfer milled granulate and sieved Stearic acid and Talc into    the Y-cone.-   4. Mix for 5 minutes.

V. Tablet Compression: Machine: Sviac

Diameter of punch: 4.0 mm (it may be changed ±10%)Tablet weight—43 mg±5%

Hardness: 3-5 kP Friability: Not More Than 1%

Disintegration: Not More Than 5 minutes

Example 11 Preparation of Rasagiline Base Tablet Cores (Citric and MalicAcids Together)

Mg/ Raw material tablet Percentage Part I, Granulation solution Citricacid 0.8 0.68 Malic acid 0.8 0.68 Rasagiline base 1.0 0.85 Part IIMannitol 79.8 68.2 Aerosil 200 0.3 0.26 Starch NF/BP 10.0 8.55Pregelatinized starch 20.0 17.09 NF/Ph. Eur Part III Aerosil 200 0.30.26 Part IV Stearic acid 2.0 1.71 Talc 2.0 1.71 Total: 117.0 100Calculated Amounts of External Excipients in Accordance with ActualAmount of Granulate

mg/ Raw material tablet ercentageP Part III Granulate Aerosil 200 0.30.26 Part IV Stearic acid 2.0 1.71 Talc 2.0 1.71

I. Granulation Solution 1 Preparation.

-   1. Weigh 80% of needed amount of Purified water into glass.-   2. Weigh into the same glass Citric acid.-   3. Insert stirrer into the glass and start to stir up to complete    solubility about 5-10 minutes.-   4. Weigh Rasagiline base and add it into the obtained Citric acid    solution.-   5. Continue stirring about 30 minutes to complete solubility of API.

II. Granulation Solution 2 Preparation.

-   1. Weigh 20% of needed amount of Purified water into the glass.-   2. Add into this glass weighed amount of Malic acid.-   3. Insert stirrer into the glass and start to stir up to complete    solubility about 5-10 minutes.

III. Granulation Preparation.

-   1. Weigh Mannitol, Aerosil 200, Starch and Pregelatinized starch and    transfer all excipients to Diosna P-6 (Diosna) and mix for 1 minute    with Mixer I (270 rpm).-   2. Mix the excipient for 1 addition minute with Mixer I (270 rpm)    and Chopper I (1500 rpm)-   3. Add Granulation solution 1 into the Diosna P-6 (Diosna) and mix    for 2 minutes with Mixer II (540 rpm) and Chopper II (2200 rpm).-   4. Clean glass after granulation solution 1 with Granulation    solution 2 and add it into the Diosna P-6(Diosna).-   5. Mix for 2 minutes with Mixer II (540 rpm) and Chopper II (2200    rpm).-   6. Transfer obtained granulate into the Glatt 1.1 (Fluid Bed) for    drying at 37° C. inlet air up to L.O.D. NMT 1.5%.

Conditions of Drying: Inlet: Min.—35° C.; Target—50° C.; Max—55° C.

Outet: Product temperature—37° C.

Flow: Min.—25; Target—60; Max—1000 IV. Milling:

Mill obtained granulate through 0.6 mm sieve using Frewitt.

V. Final Blend:

-   1. Weigh obtained amount of granulate.-   2. Calculate amounts of Aerosil 200, Stearic acid and Talc in    accordance with actual granulation weight.-   3. Screen Aerosil 200 through 50 mesh sieve.-   4. Weigh needed amount of Aerosil 200 after sieving.-   5. Transfer milled granulate and Aerosil 200 after sieving into the    Y-cone.-   6. Mix for 2 minutes.-   7. Weigh Stearic acid and Talc.-   8. Screen these excipients through 50 mesh sieve.-   9. Transfer them into the Y-cone.-   10. Mix for 5 minutes.

VI. Tablet Compression Machine: Sviac

Diameter of punch: 6.0 mm (it may be changed ±10%)Tablet weight—117 mg±5%

Hardness: 6-8 kP Friability: Not More Than 1%

Disintegration: Not More Than 5 minutes

VII. Subcoating:

Mg/tablet Raw material 4.8 Pharmacoat 606 (Hypromellose USP)Equipment: O′HARA, Peristaltic pump

1. Preparation of Sub-Coating Solution:

-   -   Pharmacoat 606 (hypromellose USP) was added into the vessel with        1510 g of Purified water and mixed for 30 minutes using stirrer.

2. Preheating:

-   -   The core tablets were placed into the Pan 2.5 kg of O′HARA        Coater and preheated:    -   Inlet air temperature—50° C. (45° to 55° C.)    -   Outlet air temperature—45° C. (40° to 50° C.).    -   Difference pressure—−50 Pa

3. Spraying Process (the Process was Continued Till Desired TabletWeight was Achieved):

-   -   Sub-coating solution was sprayed on the preheated core tablets        at the following conditions:    -   Number of spray guns—1    -   Nozzle bore—1 mm    -   Distance tablet bed/spray gun—15 cm    -   Pan speed 10 rpm (8-12 rpm)    -   Inlet air temperature—50° C. (45° to 55° C.)    -   Outlet air temperature—35° C. (30° to 40° C.)    -   Spraying rate—10-20 g/min    -   Difference pressure—−50 Pa    -   Atomizing air pressure—30 Psi    -   Pattern air pressure—30 Psi

4. Drying Process:

-   -   Inlet air temperature—45° C. (40° to 50° C.)    -   Outlet air temperature—40° C.-50° C.    -   Pan speed—5 rpm Jogging    -   Drying time—60 min

Example 12a Rasagiline base 0.5 mg Enteric Coated OptionalFormulations—with Citric Acid

This example describes 0.5 mg rasagiline base formulations withvariations in the amount of citric acid and other excipients. Theseformulations have a dissolution and pharmacokinetic profile (C_(max) andAUC) resembling that of example 1.

Per Tablet Per Tablet Per Tablet Per Tablet Component Function (mg) (mg)(mg) (mg) Core tablets Rasagiline base Drug Substance 0.5 0.5 0.5 0.5Citric acid Antioxidant 1.6 or 0.8 1.6 or 0.8 1.6 or 0.8 1.6 or 0.8Mannitol Filler 45.5 68.3 50.5 80.3 Aerosil Flowing Agent 0.4 0.6 0.40.6 Starch NF Binder 5.0 10.0 5.0 10 Starch, Disintegrant 20.0 20.0 15.020.0 Pregelatinized (Starch STA-RX 1500) Talc Lubricant 1.5 2.0 1.5 2.0Stearic Acid Lubricant 1.5 2.0 1.5 2.0 Total Core 76.0 (+/−10%) 105.0(+/−10%) 76.0 (+/−10%) 117.0 (+/−10%) Tablet Weight SubcoatingPharmacoat 606 Coating Agent 3.5 (+/−10%) 4.8 (+/−10%) 3.5 (+/−10%) 4.8(+/−10%) (Hypromellose USP) Granules Purified Water Processing AgentCoating Suspension Eudragit L-30D-55 Coating Agent 4.0 (+/−10%) 4.0(+/−10%) 4.0 (+/−10%) 6.25 (+/−10%) Talc USP Extra Fine Lubricant 1.9(+/−10%) 1.9 (+/−10%) 1.9 (+/−10%) 3.1 (+/−10%) Triethyl citrate NFPlasticizer 0.8 (+/−10%) 0.8 (+/−10%) 0.8 (+/−10%) 1.25 (+/−10%)Purified Water Processing Agent

Example 12b Rasagiline Base 1 mg Enteric Coated OptionalFormulations—with Citric Acid

This example describes 1 mg rasagiline base formulations with variationsin the amount of citric acid and other excipients. These formulationshave a dissolution and pharmacokinetic profile (C_(max) and AUC)resembling that of example 1.

Per Tablet Per Tablet Per Tablet Per Tablet Component Function (mg) (m

(mg) (mg

Core tablets Rasagiline base Drug Substance 1.0 1.0 1.0 1.0 Citric acidAntioxidant 1.6 or 0.8 1.6 or 0.8 1.6 or 0.8 1.6 or 0.8 Mannitol Filler45.0 67.8 50.0 79.8 Aerosil Flowing Agent 0.4 0.6 0.4 0.6 Starch NFBinder 5.0 10.0 5.0 10.0 Starch, Disintegrant 20.0 20.0 15.0 20.0Pregelatinized (Starch STA-RX 1500) Talc Lubricant 1.5 2.0 1.5 2.0Stearic Acid Lubricant 1.5 2.0 1.5 2.0 Total Core 76.0 (+/−10%) 105.0(+/−10%) 76.0 (+/−10%) 117.0 (+/−10%) Tablet Weight SubcoatingPharmacoat 606 Coating Agent 3.5 (+/−10%) 4.8 (+/−10%) 3.5 (+/−10%) 4.8(+/−10%) (Hypromellose USP) Granules Purified Water Processing AgentCoating Suspension Eudragit L-30D-55 Coating Agent 4.0 (+/−10%) 4.0(+/−10%) 4.0 (+/−10%) 6.25 (+/−10%) Talc USP Extra Fine Lubricant 1.9(+/−10%) 1.9 (+/−10%) 1.9 (+/−10%) 3.1 (+/−10%) Triethyl citrate NFPlasticizer 0.8 (+/−10%) 0.8 (+/−10%) 0.8 (+/−10%) 1.25 (+/−10%)Purified Water Processing Agent

indicates data missing or illegible when filed

Example 13a Rasagiline Base 0.5 mg Enteric Coated OptionalFormulations—with Malic Acid

This example describes 0.5 mg rasagiline base formulations withvariations in the amount of malic acid and other excipients. Theseformulations have a dissolution and pharmacokinetic profile (C_(max) andAUC) resembling that of example 1.

Per Tablet Per Tablet Per Tablet Per Tablet Component Function (mg) (mg)(m

(mg

Core tablets Rasagiline base Drug Substance 0.5 0.5 0.5 0.5 Malic acidAntioxidant 1.6 or 0.8 1.6 or 0.8 1.6 or 0.8 1.6 or 0.8 Mannitol Filler45.5 68.3 50.5 80.3 Aerosil Flowing Agent 0.4 0.6 0.4 0.6 Starch NFBinder 5.0 10.0 5.0 10 Starch, Disintegrant 20.0 20.0 15.0 20.0Pregelatinized (Starch STA-RX 1500) Talc Lubricant 1.5 2.0 1.5 2.0Stearic Acid Lubricant 1.5 2.0 1.5 2.0 Total Core 76.0 (+/−10%) 105.0(+/−10%) 76.0 (+/−10%) 117.0 (+/−10%) Tablet Weight SubcoatingPharmacoat 606 Coating Agent 3.5 (+/−10%) 4.8 (+/−10%) 3.5 (+/−10%) 4.8(+/−10%) (Hypromellose USP) Granules Purified Water Processing AgentCoating Suspension Eudragit L-30D-55 Coating Agent 4.0 (+/−10%) 4.0(+/−10%) 4.0 (+/−10%) 6.25 (+/−10%) Talc USP Extra Fine Lubricant 1.9(+/−10%) 1.9 (+/−10%) 1.9 (+/−10%) 3.1 (+/−10%) Triethyl citrate NFPlasticizer 0.8 (+/−10%) 0.8 (+/−10%) 0.8 (+/−10%) 1.25 (+/−10%)Purified Water Processing Agent

indicates data missing or illegible when filed

Example 13b Rasagiline Base 1 mg Enteric Coated OptionalFormulations—with Malic Acid

This example describes 1 mg rasagiline base formulations with variationsin the amount of malic acid and other excipients. These formulationshave a dissolution and pharmacokinetic profile (C_(max) and AUC)resembling that of example 1.

Per Tablet Per Tablet Per Tablet Per Tablet Component Function (mg) (mg)(mg) (mg

Core tablets Rasagiline base Drug Substance 1.0 1.0 1.0 1.0 Malic acidAntioxidant 1.6 or 0.8 1.6 or 0.8 1.6 or 0.8 1.6 or 0.8 Mannitol Filler45.0 67.8 50.0 79.8 Aerosil Flowing Agent 0.4 0.6 0.4 0.6 Starch NFBinder 5.0 10.0 5.0 10.0 Starch, Disintegrant 20.0 20.0 15.0 20.0Pregelatinized (Starch STA-RX 1500) Talc Lubricant 1.5 2.0 1.5 2.0Stearic Acid Lubricant 1.5 2.0 1.5 2.0 Total Core 76.0 (+/−10%) 105.0(+/−10%) 76.0 (+/−10%) 117.0 (+/−10%) Tablet Weight SubcoatingPharmacoat 606 Coating Agent 3.5 (+/−10%) 4.8 (+/−10%) 3.5 (+/−10%) 4.8(+/−10%) (Hypromellose USP) Granules Purified Water Processing AgentCoating Suspension Eudragit L-30D-55 Coating Agent 4.0 (+/−10%) 4.0(+/−10%) 4.0 (+/−10%) 6.25 (+/−10%) Talc USP Extra Fine Lubricant 1.9(+/−10%) 1.9 (+/−10%) 1.9 (+/−10%) 3.1 (+/−10%) Triethyl citrate NFPlasticizer 0.8 (+/−10%) 0.8 (+/−10%) 0.8 (+/−10%) 1.25 (+/−10%)Purified Water Processing Agent

indicates data missing or illegible when filed

Example 14a Rasagiline Base 0.5 mg Enteric Coated OptionalFormulations—with Both Citric and Malic Acid

This example describes 0.5 mg rasagiline base formulations withvariations in the amount of citric acid, malic acid, and otherexcipients. These formulations have a dissolution and pharmacokineticprofile (C_(max) and AUC) resembling that of example 1.

Per Tablet Per Tablet Per Tablet Per Tablet Component Function (mg) (mg)(mg) (mg) Core tablets Rasagiline base Drug Substance 0.5 0.5 0.5 0.5Malic acid Antioxidant 0.8 or 0.4 0.8 or 0.4 0.8 or 0.4 1.6 or 0.8Citric acid Antioxidant 0.8 or 0.4 0.8 or 0.4 0.8 or 0.4 1.6 or 0.8Mannitol Filler 45.5 68.3 50.5 80.3 Aerosil Flowing Agent 0.4 0.6 0.40.6 Starch NF Binder 5.0 10.0 5.0 10.0 Starch, Disintegrant 20.0 20.015.0 20.0 Pregelatinized (Starch STA-RX 1500) Talc Lubricant 1.5 2.0 1.52.0 Stearic Acid Lubricant 1.5 2.0 1.5 2.0 Total Core 76.0 (+/−10%)105.0 (+/−10%) 76.0 (+/−10%) 117.0 (+/−10%) Tablet Weight SubcoatingPharmacoat 606 Coating Agent 3.5 (+/−10%) 4.8 (+/−10%) 3.5 (+/−10%) 4.8(+/−10%) (Hypromellose USP) Granules Purified Water Processing AgentCoating Suspension Eudragit L-30D-55 Coating Agent 4.0 (+/−10%) 4.0(+/−10%) 4.0 (+/−10%) 6.25 (+/−10%) Talc USP Extra Fine Lubricant 1.9(+/−10%) 1.9 (+/−10%) 1.9 (+/−10%) 3.1 (+/−10%) Triethyl citrate NFPlasticizer 0.8 (+/−10%) 0.8 (+/−10%) 0.8 (+/−10%) 1.25 (+/−10%)Purified Water Processing Agent

Example 14b Rasagiline Base 1 mg Enteric Coated OptionalFormulations—with both Citric and Malic Acid

This example describes 1 mg rasagiline base formulations with variationsin the amount of citric acid, malic acid, and other excipients. Theseformulations have a dissolution and pharmacokinetic profile (C_(max) andAUC) resembling that of example 1.

Per Tablet Per Tablet Per Tablet Per Tablet Component Function (mg) (mg)(mg) (mg) Core tablets Rasagiline base Drug Substance 1.0 1.0 1.0 1.0Malic acid Antioxidant 0.8 or 0.4 0.8 or 0.4 0.8 or 0.4 1.6 or 0.8Citric acid Antioxidant 0.8 or 0.4 0.8 or 0.4 0.8 or 0.4 1.6 or 0.8Mannitol Filler 45.0 67.8 50.0 79.8 Aerosil Flowing Agent 0.4 0.6 0.40.6 Starch NF Binder 5.0 10.0 5.0 10.0 Starch, Disintegrant 20.0 20.015.0 20.0 Pregelatinized (Starch STA-RX 1500) Talc Lubricant 1.5 2.0 1.52.0 Stearic Acid Lubricant 1.5 2.0 1.5 2.0 Total Core 76.0 (+/−10%)105.0 (+/−10%) 76.0 (+/−10%) 117.0 (+/−10%) Tablet Weight SubcoatingPharmacoat 606 Coating Agent 3.5 (+/−10%) 4.8 (+/−10%) 3.5 (+/−10%) 4.8(+/−10%) (Hypromellose USP) Granules Purified Water Processing AgentCoating Suspension Eudragit L-30D-55 Coating Agent 4.0 (+/−10%) 4.0(+/−10%) 4.0 (+/−10%) 6.25 (+/−10%) Talc USP Extra Fine Lubricant 1.9(+/−10%) 1.9 (+/−10%) 1.9 (+/−10%) 3.1 (+/−10%) Triethyl citrate NFPlasticizer 0.8 (+/−10%) 0.8 (+/−10%) 0.8 (+/−10%) 1.25 (+/−10%)Purified Water Processing Agent

Example 15a Rasagiline Base 0.5 mg Enteric Coated OptionalFormulation—with Citric Acid, Color Coated

This example describes a 0.5 mg rasagiline base formulation containingcitric acid with an extra color coating.

Per Tablet Component Function (mg) Core tablets Rasagiline base Drug 0.5Substance Citric acid Antioxidant 1.6 Mannitol Filler 80.3 AerosilFlowing 0.6 Agent Starch, Pregelatinized Disintegrant 20.0 (StarchSTA-RX 1500) Starch NF Binder 10.0 Talc Lubricant 2.0 Stearic AcidLubricant 2.0 Total Core Tablet Weight 117.0 Subcoating Pharmacoat 606(Hypromellose Coating 4.8 USP) Granules Agent Purified Water ProcessingAgent Coating Suspension Eudragit L-30D-55 Coating 6.25* Agent Talc USPExtra Fine Lubricant 3.1 Triethyl citrate NF Plasticizer 1.25 PurifiedWater Processing Agent Top coat OPADRY II OY-GM-28900 WHITE Coating 1-5(catnum. 415850005) Agent OR OPADRY II Y-30-18037 WHITE (catnum.415880719) OR/AND Opadry fx 63f97546 silver Purified Water ProcessingAgent *Dry substance remaining on the core.

Example 15b Rasagiline Base 1 mg Enteric Coated OptionalFormulation—with Citric Acid, Color Coated

This example describes a 1 mg rasagiline base formulation containingcitric acid with an extra color coating.

Per Tablet Component Function (mg) Core tablets Rasagiline base Drug 1.0Substance Citric acid Antioxidant 1.6 Mannitol Filler 79.8 AerosilFlowing 0.6 Agent Starch, Pregelatinized Disintegrant 20.0 (StarchSTA-RX 1500) Starch NF Binder 10.0 Talc Lubricant 2.0 Stearic AcidLubricant 2.0 Total Core Tablet Weight 117.0 Subcoating Pharmacoat 606(Hypromellose Coating 4.8 USP) Granules Agent Purified Water ProcessingAgent Coating Suspension Eudragit L-30D-55 Coating 6.25* Agent Talc USPExtra Fine Lubricant 3.1 Triethyl citrate NF Plasticizer 1.25 PurifiedWater Processing Agent Top coat Opadry ® II 31F20721 Blue Coating 1-5 ORAgent Opadry ® II 34G24627 Pink OR/AND Opadry fx 63f97546 silverPurified Water Processing Agent *Dry substance remaining on the core.

Example 16a Rasagiline Base 0.5 mg Enteric Coated OptionalFormulation—with Malic Acid, Color Coated

This example describes a 0.5 mg rasagiline base formulations containingmalic acid with an extra color coating.

Per Tablet Component Function (mg) Core tablets Rasagiline base Drug 0.5Substance Malic acid Antioxidant 1.6 Mannitol Filler 80.3 AerosilFlowing 0.6 Agent Starch, Pregelatinized Disintegrant 20.0 (StarchSTA-RX 1500) Starch NF Binder 10.0 Talc Lubricant 2.0 Stearic AcidLubricant 2.0 Total Core Tablet Weight 117.0 Subcoating Pharmacoat 606(Hypromellose Coating 4.8 USP) Granules Agent Purified Water ProcessingAgent Coating Suspension Eudragit L-30D-55 Coating 6.25* Agent Talc USPExtra Fine Lubricant 3.1 Triethyl citrate NF Plasticizer 1.25 PurifiedWater Processing Agent Top coat OPADRY II OY-GM-28900 WHITE Coating 1-5(catnum. 415850005) Agent OR OPADRY II Y-30-18037 WHITE (catnum.415880719) OR/AND Opadry fx 63f97546 silver Purified Water ProcessingAgent *Dry substance remaining on the core.

Example 16b Rasagiline Base 1 mg Enteric Coated OptionalFormulation—with Malic Acid, Color Coated

This example describes a 1 mg rasagiline base formulations containingmalic acid with an extra color coating.

Per Tablet Component Function (mg) Core tablets Rasagiline base Drug 1.0Substance Malic acid Antioxidant 1.6 Mannitol Filler 79.8 AerosilFlowing 0.6 Agent Starch, Pregelatinized Disintegrant 20.0 (StarchSTA-RX 1500) Starch NF Binder 10.0 Talc Lubricant 2.0 Stearic AcidLubricant 2.0 Total Core Tablet Weight 117.0 Subcoating Pharmacoat 606(Hypromellose Coating 4.8 USP) Granules Agent Purified Water ProcessingAgent Coating Suspension Eudragit L-30D-55 Coating 6.25* Agent Talc USPExtra Fine Lubricant 3.1 Triethyl citrate NF Plasticizer 1.25 PurifiedWater Processing Agent Top coat Opadry ® II 31F20721 Blue Coating 1-5 ORAgent Opadry ® II 34G24627 Pink OR/AND Opadry fx 63f97546 silverPurified Water Processing Agent *Dry substance remaining on the core.

Example 17 Extraction of Rasagiline Base from Tablets

The aim of the study was to evaluate the amount of free Rasagiline basein 1 mg tablets of “Citric” formulation.

Rasagiline is assumed to present in the formulation in salt form or asfree base.

Rasagiline base is a non-polar compound very soluble in non-polarorganic solvents such as hexane toluene and ethylacetate. Therefore,free Rasagiline base could be extracted from the solid formulation bythese solvents.

Rasagiline salts are not soluble in non-polar solvents and probabilityof the extraction of rasagiline citrate with hexane, toluene, 1-octanolor ethylacetate is very low.

Core tablets of Rasagiline base prepared using steps described inexample 9 were tested. Each tablet contained 1 mg of Rasagiline base.Placebo tablets were used as references.

17 core tablets, 1 mg of Rasagiline base each were crushed and ground inmortar to homogeneous fine powder.

Each powder was mixed with 20 ml of organic solvent and stirred withmagnetic stirrer for 1 hour at room temperature in closed glass vessel.Then the mixture was settled without stirring, the clear liquid wasdecanted and a sample of the resulting extract was filtered trough 0.2μfilter.

The filtered samples of the extracts were subjected to HPLC analysis forquantity of dissolved Rasagiline. Samples of the placebo extracts wereused as control.

Maximal possible calculated concentration of Rasagiline base in theextracts is 0.85 mg/ml (17 mg in 20 ml solvent).

The results are summarized in Table 5 below.

TABLE 5 Extractions of Rasagiline base from core tablets with organicsolvents Achieved Weight concentration of Experiment No. of ofRasagiline in No. tablets tablets, g Solvent extract, mg/ml 1 17 2.02Toluene 0.01 2 17 2.02 n-Hexane 0.01 3 17 2.02 DCM 0.01 4 17 2.031-Octanol 0.01 5 17 2.02 Ethyl 0.02 acetate

Summary of Results

The experimental results in Table 5 show that the core tablets of“Citric” formulation of Rasagiline base may contain 1 to 2 percent ofthe free rasagiline base extractable with non polar solvents.

Amount of the extractable base does not depend on the solvent type fornon polar solvent as n-hexane, toluene, 1-octanol and dichloromethane.

At the same time more polar solvent as ethylacetate extracted moreRasagiline from the core tablets.

Example 18 Clinical Study Based on Tablets According to Examples 3a and3b

This study evaluates the bioavailability of two different rasagilinebase 1 mg enteric coated tablet formulations prepared according to eachof Examples 3a (Formulation I) and 3b (Formulation III) verses themarketed rasagiline drug product (Azilect 1 mg) following a single doseadministration, and to assess the effect of food on each one of the testformulations.

This study also evaluates the safety and tolerability of each treatment.

1. Study Design

This study is a flexible two-part protocol, each part testing thebioavailability of a different rasagiline base 1 mg enteric coatedformulation (Formulation I or Formulation III) against the referenceproduct (Azilect® 1 mg).

Each part is an open-label, three-period, three-sequence, comparativecrossover study in 15 healthy males and females (5 per sequence).

Treatment A: One Rasagiline Base 1 mg Enteric Coated Tablets (testFormulation I or test Formulation III) in the fasted state.Treatment B: One Azilect® tablet (reference 1 mg rasagiline asrasagiline mesylate) in the fasted state.Treatment C: One Rasagiline Base 1 mg Enteric Coated Tablets (testFormulation I or test Formulation III) following a standardizedhigh-fat, high-calorie meal.

The 3 treatments are administered across 3 study periods each of whichis separated by a 14-day washout interval. They are administeredaccording to one of three sequences to which subjects are randomlyassigned: A-B-C, B-C-A, or C-A-B.

In each period, subjects are confined for two overnight stays [at least10.5 hours prior to and until at dose administration]. Subjects returnfor an ambulatory blood sample collection (36 hours) on Day 2.

In Part 1, Subjects 1-15 receive test Formulation I or reference, whilein Part 2, Subjects 16-30 receive test Formulation III or reference. Thedecision to proceed with each study part is based on the availability ofthe test Formulation.

AEs, vital signs, physical examination, and clinical laboratory testsare assessed for safety and blood samples are taken at regularpre-defined time points throughout the study for the measurement ofrasagiline and aminoindan concentrations in plasma.

2. Subject Selection

Thirty (30) healthy adult (˜50%/50% male and female) subjects areselected from non-institutionalized subjects consisting of members ofthe community at large.

3. Pharmacokinetic (PK) Sampling and Analysis

A total of 80 samples (about 400 mL) are drawn from each subject for PKpurposes. Pharmacokinetic sampling occurs at the following timepoints:

a) Treatment A (Test, Fasted):

-   -   Day 1 within 90 minutes prior to dosing (0 hour) and after dose        administration at 0.5, 0.75, 1, 1.33, 1.67, 2, 2.33, 2.67, 3,        3.33, 3.67, 4, 4.5, 5, 6, 7, 8, 9, 12, 24 and 36 hours (22        samples).

b) Treatment B (Reference, Fasted):

-   -   Day 1 within 90 minutes prior to dosing (0 hour) and after dose        administration at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6,        7, 8, 12, 24 and 36 hours (17 samples).

c) Treatment C (Test, Fed):

-   -   Day 1 within 90 minutes prior to dosing (0 hour) and after dose        administration at 1, 1.5, 2, 2.5, 3, 3.33, 3.67, 4, 4.33, 4.67,        5, 5.33, 5.67, 6, 6.33, 6.67, 7, 7.33, 7.67, 8, 8.5, 9, 10, 11,        12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26 and 36        hours (41 samples).

Blood are drawn either by direct venipuncture or through an indwellingintravenous cannula. Whenever the latter is performed, the cannula isflushed with 1.5 mL normal saline after each sampling. In addition, toavoid sample dilution, 1 mL blood is discarded before the next sample(as long as the cannula is in place). Therefore, up to 5 mL blood iscollected at each time point. The total blood volume taken per subjectfor pharmacokinetic sampling is approximately 400 ml over a 4-weekperiod.

Samples are collected into appropriate volume K2-EDTA vacutainers. Thelabels for all biological sample collection and storage containerscontain, at a minimum, Protocol Number, Sub-study number, SubjectNumber; Dosing Period; Dosing Day; PK time point. Immediately followingsample collection, samples are mixed by inverting the collection tube atleast 2-3 times. Samples are cooled by an ice bath or cooling deviceuntil processed. Blood processing occur within 2 hours of collection:the sample is centrifuged at approximately 2000 g and 4° C. (±3° C.) forabout 10 minutes, the plasma transferred into appropriately labeledduplicate polypropylene tubes, and stored at approximately −20° C. untiltransfer or shipment to the bioanalytieal laboratory. At least 0.7 mL ofplasma is transferred into the first polypropylene tube and theremaining plasma is transferred to the second polypropylene tube. Thetime at which samples are placed at −20° C. are recorded in the studydocumentation.

Actual sampling time is recorded directly in the source data or CRF.Sample processing procedures are documented in the PK logbook.

The rasagiline and aminoindan plasma concentrations are measured using avalidated LC/MS/MS bioanalytical method and according to theBioanalytical Laboratory's Standard Operating Procedures and FDAGuidelines.

Analysis of the PK data of each sub-study is performed separately,according to audited bioanalytical data availability. The individualplasma concentrations of rasagiline and aminoindan are listed, displayedgraphically as appropriate and summarized using descriptive statisticsfor each of the treatments.

Pharmacokinetic analysis are performed with rasagiline and aminoindanconcentration profiles using appropriate non-compartmental methods.

The following parameters are calculated: C_(max), t_(max), t_(lag),AUC_(t), AUC_(∞), t_(1/2), CL/F, V/F, % AUC_(ext), regressioncoefficient of the terminal slope. Additional PK parameters will becalculated if deemed necessary. All the PK parameters are listed andsummarized using descriptive statistics.

Statistical analysis is performed using SAS for each substudy based onthe reception of the data. For each sub-study, bioequivalence betweenthe test and reference formulations in the fasted state and the foodeffect on the test formulation are evaluated only for rasagiline,according to 90% confidence intervals (CIs) of ratios of geometric meansfor C_(max), AUC_(t), and AUCoo. The ratios and CI are calculated usingANCOVA on the log-transformed data (MIXED procedure, SAS). Theconclusion regarding bioequivalence are based on the back-transformedpoint estimate and CI. T_(max) are analyzed using nonparametric analysis(Wilcoxon Signed Rank Test).

4. Results Bioequivalence Tests

The testing results show that the delayed release formulations tested(Formulation I and Formulation III) meets the criteria forbioequivalence to the known immediate release formulation. Each of theC_(max) and AUC_(t) achieve a range of 80-140% within a 90% confidenceinterval between the formulation tested and the reference immediaterelease formulation.

MAO Assay:

The testing results show MAO-B activity for formulation preparedaccording to each of the Examples 3a and 3b are comparable to thereference immediate release formulation.

The standard method is used for the enzymatic determination of MAO:“Determination of monoamine oxidase (MAO) by an extraction method usingradiolabelled substrate in various tissues”.

Briefly, fifty (50) μl of homogenate are added to 100 μl 0.1 M phosphatebuffer (pH-7.4). After preincubation of 20 minutes at 37° C., 50 μl of¹⁴C-phenylethylamine hydrochloride (10 μM final concentration) are addedand incubation continued for next 20 minutes. The reaction is thenstopped by addition of citric acid 2 M.

Radioactive metabolites are extracted into toluene/ethyl acetate (1:1v/v.), a solution of 2,5-diphenyloxazole is added to a finalconcentration of 0.4% and the metabolite content is estimated by liquidscintillation counting.

Activity of rat brain homogenate serves as standard (positive control)to the assay.

Protein determination is performed by the Lowrey method.

Safety and Tolerability

The testing results show that safety and tolerability for each treatmentare acceptable.

Example 19 Additional Studies Based on Tablets According to Examples 3c,3d, 6a-6d and 9-16

Additional studies are conducted evaluating the bioavailability of twodifferent rasagiline base 1 mg enteric coated tablet formulationsprepared according to each of Examples 3c, 3d, 6a-6d and 9-16 verses themarketed rasagiline drug product (Azilect 1 mg) following a single doseadministration, and the effect of food on each one of the testformulations.

The results show that all of these formulations tested have acceptablebioavailability characteristics and MAO-B activity.

1.-36. (canceled)
 37. A stable oral dosage form comprising a core havingrasagiline malate and at least one pharmaceutically acceptableexcipient; and an acid resistant pharmaceutically acceptable coating.38. A stable oral dosage form comprising a core having rasagiline baseand at least one pharmaceutically acceptable excipient; and an acidresistant pharmaceutically acceptable coating.
 39. Rasagiline citrate.